The present invention relates to a process for the synthesis of montelukast, a pharmaceutical agent, as well as to intermediates useful in the process.
Montelukast, chemically [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropane acetic acid, has the following structure of formula (1):

Montelukast monosodium salt (montelukast sodium) is commonly used for treatment of asthma. It is marketed under the brand name SINGULAIR® (Merck) in the form of oral tablets, chewable tablets, and granules.
U.S. Pat. No. 5,565,473 to BELLEY et al. (see also corresponding EP 0 480 717) discloses a genus of pharmaceutically useful compounds that encompasses montelukast and salts thereof. Example 161 in connection with example 146 of U.S. Pat. No. 5,565,473 disclose the synthesis of montelukast sodium as follows:
THP as used herein means tetrahydropyranyl group, typically of the formula:
wherein the asterisk indicates a chiral carbon atom.
Many other synthetic schemes are proposed in U.S. Pat. No. 5,565,473 for making unsaturated hydroxyalkylquinoline acids, which may generically include montelukast. However, none of these other schemes were specifically applied to making montelukast. For example, Method B in U.S. Pat. No. 5,565,473 comprises reacting a compound of “general formula (XII)” with an organometallic compound of formula R2M to give a compound of “general formula (Ia)”. Applying the corresponding substituent groups for montelukast, the method would follow the scheme below, wherein the compound of formula (2) is the representative compound of “general formula (XII)”:
M is suggested to be MgBr or Li in Method A. The only disclosed process for making the compounds of “general formula (XII)” is not desirable for making montelukast, i.e. for making the hypothetical compound of formula (2). Specifically the process in Method B calls for a coupling reaction with a compound of “general formula (XI).” If applied to the corresponding substituents for montelukast, the reaction would be as follows:
But this process cannot provide the compound (2) in the rigid R-configuration as suggested above, which is required for the montelukast synthesis. Instead, only a racemic product may be obtained and no method has been suggested how to resolve the racemate into single enantiomers.
Thus, there exists a need for providing a suitable process for making the compound of formula (2) and for providing conditions for its conversion to montelukast of formula (1).